In patients with advanced NSCLC (aNSCLC), the impact of KRAS mutations (m) and comutations with STK11 and KEAP1 on outcomes across different PD-L1 levels remains incompletely understood. We aimed to investigate the frequency of KRAS mutations and comutations across PD-L1 levels, and the association between these mutations and survival, stratified by PD-L1 expression. We conducted a nationwide cohort study of patients diagnosed with aNSCLC between 2016 and 2021 treated with frontline (chemo)immunotherapy, who underwent molecular genotyping including KRAS, STK11, and KEAP1. Real-world overall survival (OS) and progression-free survival (rwPFS) were estimated using Kaplan-Meier methodology. Cox multivariable regressions were used to evaluate the association between KRASm and survival across different PD-L1 strata, and to assess whether the association between KRASm and survival differed by PD-L1 level. Finally, within subgroups defined by PD-L1 expression, we used interaction terms to assess whether co-mutations with STK11 and KEAP1 moderated the association between KRAS mutation and survival. Of our 2593-patient cohort, 982 (37.9 %) were KRASm and 1611 (62.1 %) KRASwt. KRASm were enriched in the PD-L1 ≥50 % cohort (334/743, 45 %), but within patients with KRASm, co-mutations with STK11 and KEAP1 were enriched in the PD-L1 0 % cohort. KRASm was associated with significantly worse OS in the PD-L1 0 % cohort compared to the PD-L1 ≥50 % cohort (P for interaction = 0.008). On adjusted analyses stratified by PD-L1, KRASm was associated with worse survival only in the PD-L1 0 % group (OS HR 1.46, p = 0.001). KEAP1 and STK11 comutations were most strongly associated with worse OS in the PD-L1 0 % subgroup; patients with triple KRASm/KEAPm/STK11m PD-L1 0 % NSCLC experienced the worst outcomes. KRASm are associated with worse overall survival in PD-L1 negative NSCLC; however, this association is largely driven by comutations with STK11 and KEAP1, which are enriched in PD-L1 negative tumors.

中文翻译：

---

具有 KRAS 突变和 STK11/KEAP1 突变（跨 PD-L1 水平）的晚期 NSCLC 患者接受一线免疫检查点抑制 (ICI) 治疗的结果

在晚期 NSCLC (aNSCLC) 患者中，KRAS 突变 (m) 以及 STK11 和 KEAP1 突变对不同 PD-L1 水平的结果的影响仍不完全清楚。我们的目的是研究 KRAS 突变和 PD-L1 水平突变的频率，以及这些突变与生存之间的关联，并按 PD-L1 表达进行分层。我们对 2016 年至 2021 年间诊断为非小细胞肺癌并接受一线（化学）免疫治疗的患者进行了一项全国性队列研究，这些患者接受了包括 KRAS、STK11 和 KEAP1 在内的分子基因分型。使用 Kaplan-Meier 方法估计现实世界的总生存期 (OS) 和无进展生存期 (rwPFS)。 Cox 多变量回归用于评估 KRASm 与不同 PD-L1 层的生存之间的关联，并评估 KRASm 与生存之间的关联是否因 PD-L1 水平而异。最后，在由 PD-L1 表达定义的亚组中，我们使用交互术语来评估 STK11 和 KEAP1 的共突变是否调节 KRAS 突变与生存之间的关联。在我们的 2593 名患者队列中，982 名 (37.9%) 为 KRASm，1611 名 (62.1%) 为 KRASwt。 KRASm 在 PD-L1 ≥ 50 % 队列中富集（334/743，45 %），但在 KRASm 患者中，与 STK11 和 KEAP1 的共突变在 PD-L1 0 % 队列中富集。与 PD-L1 ≥ 50 % 队列相比，KRASm 与 PD-L1 0 % 队列中的 OS 显着较差相关（交互作用 P = 0.008）。根据 PD-L1 分层调整分析，KRASm 仅在 PD-L1 0% 组中与较差的生存率相关（OS HR 1.46，p = 0.001）。 KEAP1 和 STK11 突变与 PD-L1 0 % 亚组中较差的 OS 密切相关；三重 KRASm/KEAPm/STK11m PD-L1 0 % NSCLC 患者的预后最差。 KRASm 与 PD-L1 阴性 NSCLC 的总体生存率较差有关；然而，这种关联很大程度上是由 STK11 和 KEAP1 的突变驱动的，而 STK11 和 KEAP1 在 PD-L1 阴性肿瘤中富集。